Approximately one in 36 men carry two copies of a minor alteration in the HFE gene, which can significantly increase their likelihood of developing dementia, as revealed by new research involving nearly 12,200 Australians and Americans.
Dementia currently impacts around 433,000 individuals in Australia. While it is more common in women, this new genetic insight indicates that older men with this variant may face a more pronounced risk of memory loss.
HFE Gene, Men, and Dementia
The haemochromatosis gene regulates iron levels in the body, but its H63D variant is surprisingly prevalent, appearing in one out of three people as a single copy, and in about one in 36 as a double copy. Contrary to the more notorious C282Y variant, H63D doesn’t typically overload the liver, yet tests indicate it can disturb cellular iron sensors, leading to harmful reactions due to excess iron.
Genes, Iron, Brains, and Memory
Iron is essential but can be unstable; when it accumulates in microglia, the immune cells of the brain, it can lead to oxidative stress and inflammation associated with Alzheimer’s disease. Both animal and human studies support this connection: iron imbalances may produce reactive oxygen species that damage neurons and could trigger ferroptosis, a specific type of cell death related to cognitive decline.
Moreover, HFE variants have been associated with Parkinson’s disease and motor neuron disorders, hinting that improper iron management might contribute to several neurological conditions. Research indicates that abnormal iron levels in crucial brain areas correlate with earlier onset and quicker progression of these diseases among those with genetic predispositions.
What the ASPREE Data Revealed
The ASPREE trial followed over 19,000 healthy seniors for about 6.4 years to assess low-dose aspirin’s effects, inadvertently providing valuable data on aging. Genome analyses from ASPREE showed that men with two H63D copies have a 2.39 times higher risk of developing dementia compared to those without the variant, while women with the same genotype did not exhibit any increased risk.
“Men with two copies of this variant have more than double the risk of dementia, contrasting with women,” noted a professor involved in the study.
Why Only Men?
Factors like menstruation and pregnancy offer women a natural way to regulate iron, which might lessen the variant’s impact; complications related to haemochromatosis typically manifest later and are less severe in women. Imaging studies show that women who cease menstruation early tend to accumulate more iron in deep brain structures, implying that prolonged iron exposure could be a crucial factor affecting brain health in men.
Sex hormones also play a role: estrogen influences iron metabolism and provides anti-inflammatory effects that could protect brain circuits. Although HFE analysis is a routine part of diagnostics for suspected iron overload, these new findings suggest it may be beneficial to broaden screening for aging men, potentially uncovering hidden dementia risks before they become apparent.
Identifying carriers is relatively inexpensive and, importantly, this could point to actionable steps concerning iron management and its associated inflammatory consequences.
Practical Steps Today
Interestingly, the research team found no clear connection between blood ferritin levels and dementia. However, maintaining normal iron levels, treating chronic inflammation, being physically active, and focusing on a plant-based diet are all beneficial for brain health. Regular exercise can lower dementia risk by about 30 percent, according to estimates from health organizations.
Healthcare providers also promote monitoring blood pressure, quitting smoking, and fostering social connections—all of which benefit older adults, regardless of their genetic background.
Current dementia prevention tactics often revolve around general lifestyle suggestions or age markers, but this variant highlights the importance of gender-aware screening approaches. If men carrying double H63D copies truly have twice the risk, early genetic testing could lead them to more proactive preventative strategies long before any symptoms surface.
Men, Dementia, and the Future
A professor from a renowned university hopes that delving into how H63D alters brain pathways will pave the way for treatments that can mitigate the damage even without altering the gene itself. Future research aims to follow variant carriers with MRI scans and fluid markers to detect early signs of inflammation, subsequently testing whether dietary changes, blood removal procedures, or specific drugs can help balance aging toward healthier outcomes.
This research provides a significant genetic insight that is particularly relevant for the current generation of men approaching their 70s.
